Review

Respiration 2018;96:283–301 Received: April 23, 2018

Accepted: April 23, 2018
DOI: 10.1159/000489501 Published online: June 28, 2018

Diagnosis and Management of Systemic

Endemic Mycoses Causing Pulmonary
Disease
Helmut J.F. Salzer a, b Gerd Burchard c Oliver A. Cornely d
     

Christoph Lange a, b, e, f Thierry Rolling c, g Stefan Schmiedel g Michael Libman h

       

Domenico Capone i, j Thuy Le k, l Margareth P. Dalcolmo m Jan Heyckendorf a, b

       

a Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany; b German Center for Infection
   

Research, Clinical Tuberculosis Center, Borstel, Germany; c Bernhard Nocht Institute for Tropical Medicine, Hamburg,
 

Germany; d Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical
 

Trials Centre Cologne (ZKS Köln), University of Cologne and Department I of Internal Medicine, ECMM Excellence
Center of Medical Mycology, University Hospital of Cologne, Cologne, Germany; e International Health/Infectious
 

Diseases, University of Lübeck, Lübeck, Germany; f Department of Medicine, Karolinska Institutet, Stockholm,
 

Sweden; g Section of Infectious Diseases and Tropical Medicine, 1st Department of Internal Medicine, University
 

Medical Centre Hamburg-Eppendorf, Hamburg, Germany; h J.D. MacLean Centre for Tropical Diseases, McGill
 

University, Montreal, QC, Canada; i Pulmonology and Radiology Services, Rio de Janeiro State University, Rio de
 

Janeiro, Brazil; j Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; k Division of Infectious Diseases, Duke
   

University School of Medicine, Durham, NC, USA; l Wellcome Trust Major Overseas Programme, Oxford University
 

Clinical Research Unit, Ho Chi Minh City, Vietnam; m Helio Fraga Reference Center, FIOCRUZ, Rio de Janeiro, Brazil
 

Keywords while histoplasmosis and blastomycosis also occur predom-

Endemic mycoses · Pulmonary disease · Diagnosis ·
Management · Treatment
Abstract
Systemic endemic mycoses cause high rates of morbidity
and mortality in certain regions of the world and the real im-
pact on global health is not well understood. Diagnosis and
management remain challenging, especially in low-preva-
lence settings, where disease awareness is lacking. The main
challenges include the variability of clinical presentation, the
fastidious and slow-growing nature of the fungal pathogens,
the paucity of diagnostic tests, and the lack of options and
toxicity of antifungal drugs. Coccidioidomycosis and para-
coccidioidomycosis are restricted to the Americas only, and
inantly in the Americas, these mycoses have also been re-
ported on other continents, especially in sub-Saharan Africa.
Talaromycosis is endemic in tropical and subtropical regions
in South-East Asia and southern China. Systemic endemic
mycoses causing pulmonary disease are usually acquired via
the airborne route by inhalation of fungal spores. Infections
can range from asymptomatic or mild with flu-like illnesses
to severe pulmonary or disseminated diseases. Skin involve-
ment is frequent in patients with paracoccidioidomycosis,
blastomycosis, sporotrichosis, and talaromycosis and mani-
fests as localized lesions or diffuse nodules in disseminated
disease, but can also occur with other endemic mycoses. Cul-
ture and/or characteristic histopathology from clinical sam-
ples is the diagnostic standard for endemic mycoses. Immu-
nological assays are often not available for the diagnosis of

© 2018 S. Karger AG, Basel Helmut J.F. Salzer, MD, MPH

Division of Clinical Infectious Diseases, Research Center Borstel
Leibniz Lung Center, Parkallee 35
E-Mail karger@karger.com
DE–23845 Borstel (Germany)
www.karger.com/res
E-Mail hsalzer @ fz-borstel.de
most endemic mycoses and molecular amplification meth-
ods for the detection of fungal nucleic acids are not stan-
dardized at present. The first-line treatment for mild to mod-
erate histoplasmosis, paracoccidioidomycosis, blastomyco-
sis, sporotrichosis, and talaromycosis is itraconazole. Severe
illness is treated with amphotericin B. Patients with severe
coccidioidomycosis should receive fluconazole. Treatment
duration depends on the specific endemic mycosis, the se-
verity of disease, and the immune status of the patient, rang-
ing between 6 weeks and lifelong treatment.
© 2018 S. Karger AG, Basel
Introduction
Systemic endemic mycoses include a group of dimor-
phic fungi that are found in distinct geographical regions.
Paracoccidioidomycosis and talaromycosis are found in
tropical and sub-tropical regions, while coccidioidomy-
cosis is found in warm and dry climates of semi-deserts
and blastomycosis in temperate climates. Histoplasmosis
occurs under variable conditions ranging from tropical to
temperate climates. The impact of climate change and
changes due to migration is uncertain and the real global
burden of endemic mycoses is not well understood [1].
Inhalation of fungal spores may cause infection. Clini-
cal presentation can vary from asymptomatic to dissemi-
nated fatal disease and depends on the immune status of
the host and the infectious dose from the environmental
exposure. Most endemic mycoses, including histoplasmo-
sis, coccidioidomycosis, blastomycosis, and sporotricho-
sis, are capable of causing large outbreaks. Diagnosis of
a b
Fig. 1. a Chest X-ray showing macronodular infiltrates in both upper lobes. b Corresponding CT scan of the chest
showing two macronodular consolidations on the right side, smaller nodules, and traction bronchiectasis mim-
icking pulmonary tuberculosis in a patient with histoplasmosis.
284 Respiration 2018;96:283–301
DOI: 10.1159/000489501
systemic endemic mycoses causing pulmonary disease is
challenging, because mycoses may resemble other diseas-
es (e.g., pulmonary tuberculosis, bacterial or viral pneu-
monia, lung cancer) (Fig. 1), and physicians in low-prev-
alence settings may not be familiar with the disease mani-
festations. Establishing a diagnosis is further complicated
by the difficulty in growing these organisms and by the
paucity of nonculture-based diagnostic assays, specifically
the lack of standardization of serological and molecular
tests. Pathologists may not be familiar with the histopath-
ological features. Furthermore, disease management is of-
ten complex, including long-term antifungal treatment,
drug-drug interactions, therapeutic drug monitoring
(TDM), frequent follow-ups to monitor for antifungal
side effects, and disease relapse and complications.
The aim of this review is to guide physicians in the di-
agnosis and management of systemic endemic mycoses
causing pulmonary disease. It should raise awareness
about important disease characteristics (Tables 1, 2), diag-
nostic tests (Table 3), and antifungal treatment (Table 4).
Disease Characteristics
Histoplasmosis
Histoplasmosis caused by the dimorphic fungus His-
toplasma capsulatum is found worldwide, but particular-
ly in North, Central, and South America (Table 1). It has
been reported from parts of southern and eastern Europe,
Africa, Asia, and Australia; however, reports are usually
limited to a few cases [2]. It has the potential to cause
larger outbreaks [3].
Salzer et al.
Table 1. Disease characteristics

Species Endemic areas Reservoir Route of Populations Prevention Commentary

transmission at risk

Histoplasmosis Histoplasma capsula- North and Central America, Soil, animal drop- Aerogenic Local population, travelers Immunocompromised Disease severity partly
tum sensu latu Africa (Central, South, West) pings (bats), caves, to endemic regions (visit- individuals should avoid depends on amount of
– Histoplasma capsu- caverns, abandoned ing caves, abandoned activities with disturbing inoculum and host im-
latum var. capsulatum buildings buildings, construction material/soil in regions of mune status
– Histoplasma capsula- works) high prevalence
tum var. duboisi (=
African histoplasmo-
sis)
– Others

Paracocci- Paracoccidioides brasil- South America (Brazil, Peru, Soil Aerogenic Local population, especially Human infections are not In some endemic (rural,
dioidomycosis iensis, Argentina, Colombia, Ecuador, smokers with COPD, work- contagious humid) areas of Brazil
Paracoccidioides lutzii Venezuela) ers in rural areas (e.g., incidence close to 40 cas-
farmers), few cases in trav- es/100,000 inhabitants;
elers very high male to female
ratio

Coccidioido- Coccidioides immitis, Southwestern USA – Arizona
mycosis Coccidioides posadasii (66% of cases), central and
southern California (31% of
cases), New Mexico, Texas, few
cases from Washington, Utah
– Mexico, Central and South
America
Soil of certain arid Aerogenic, inhala- Persons after exposure in Residents can avoid ac- Approximately 2/3 of
areas tion of dust (con- endemic regions (highest in tivities that expose them persons experience few or
struction, landscap- dry periods following a to dust or desert soil and no symptoms
ing, farming, ar- rainy season), often associ- stay indoors during dust
chaeology, ated with outdoor activities storms. Laboratory per-
excavation, recre- and dust; very rare cases in sonnel handling the or-
ational pursuits) or travelers ganism should practice
from dust clouds biosafety level 3 precau-
(earthquakes, wind- tions
storms)

Blastomycosis Blastomyces dermatiti- South-Eastern and South-Cen-
dis, tral states of the USA and Ca-
Blastomyces gilchristii nadian provinces bordering the
Great Lakes, and New York
state and Canada along the St.
Lawrence River and the Nelson
River
Soil containing de- Aerogenic, skin No special population, Human infections are not
caying vegetation or inoculation often seen in children, can contagious, immunocom-
decomposed wood, be opportunistic in immu- promised individuals
associated with wa- nocompromised hosts should avoid activities
terways with disturbing material/
soil in regions of high
prevalence

Sporotrichosis Sporothrix schenckii, Found worldwide from tem- Soil, moss, decaying Skin inoculation, No special population, Skin protection in people
Sporothrix brasiliensis, perate to tropical climate, en- wood and vegetation aerogenic higher risk for immuno- working in gardening or
Sporothrix globose, demic in Peru compromised patients landscaping
Sporothrix mexicana

Talaromycosis Talaromyces marneffei Southeast Asia, northeastern Bamboo rats, soil in Aerogenic, skin Residents and travelers in Transmission has been
(formally Penicillium India, and southern China bamboo rat burrows, inoculation endemic regions who are reported
marneffei) soil enriched with immunocompromised,
animal excreta especially patients with
advanced HIV infection

AIDS, acquired immune deficiency syndrome; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency syndrome.

a b

Fig. 2. Diffuse small nodules in both lungs on chest X-ray (a) and axial CT scan of the chest (b) mimicking mil-
iary tuberculosis in a patient with histoplasmosis.

Systemic Endemic Mycoses Causing Respiration 2018;96:283–301 285

Pulmonary Disease DOI: 10.1159/000489501
Table 2. Symptoms and radiological patterns of systemic endemic mycoses causing pulmonary disease
Clinical presentation
Histo- – Acute diffuse pulmonary disease
plasmosis (infiltrates)
– Acute localized pulmonary disease
(localized infiltrates, mediastinal
lymphadenopathy)
– Chronic cavitary
– Mediastinal syndromes (e.g., medi-
astinitis, fibrosis)
– Broncholithiasis
– Nodules
Paracoccidio- Acute/subacute form (juvenile) (5–
idomycosis 25%)
– Lymphadenopathy, hepatospleno-
megaly
– Cutaneous lesions, fistula formation
– Rarely pulmonary involvement
Chronic form (adult) (74–96%)
– Pulmonary (77%)
– Other organs (skin, etc.)
Coccidio- Primary infection: mostly with pul-
idomycosis monary involvement
Extrapulmonary infection: indolent
course
Blastomycosis Pulmonary disease (90%)
Extrapulmonary disease
Sporotrichosis Lymphocutaneous: most common
Pulmonary infection mainly in
COPD and alcohol use
Osteoarticular infection: in particular
joints
CNS: meningitis is rare
Dissemination: in patients with ad-
vanced HIV infection
Talaromycosis Localized disease: seen in non-HIV-
infected persons
Disseminated disease most common
in patients with advanced HIV infec-
tion
CNS, central nervous system; CPA, chronic pulmonary aspergillosis; TB, tuberculosis.
286 Respiration 2018;96:283–301
DOI: 10.1159/000489501
Most frequent
symptoms
Asymptomatic or
mild “flu-like symptoms”
Respiratory symptoms
Skin lesions
Estimated 2/3 of patients are asymp-
tomatic
Fever, cough, chest pain, and arthal-
gias in primary infection
Erythema nodosum
Pulmonary: nonspecific, cough, fever, Mostly pulmonary, but frequent-
night sweats, weight loss, chest pain, ly skin involvement, sometimes
and hemoptysis
Lymphocutaneous: ulcerative or
nodular lesions, lymphangitis
Pulmonary: fever, cough night
sweats, weight loss
Osteoarticular: pain, swelling, de-
creased range of motion, draining
sinuses in affected joints
Localized disease: depends on organ
involved
Disseminated disease: fever, fatigue,
weight loss, lymphadenopathy, hepa-
tosplenomegaly, skin lesions (primar-
ily on the face)
Organ involvements Chest radiological pattern Commentary
Pulmonary Diffuse infiltrates, opacities, small or large Immunosuppression as risk
dissemination to any organ nodules, mediastinal mass, cavities (in factor for severe disease with
(e.g., eye) chronic pulmonary disease), lymph node dissemination (e.g., advanced
enlargement HIV infection)
Lymphatic system (lymph nodes, Consolidations (75%), multiple nodules, More severe in immunocom-
liver, spleen, bone marrow, skin, interlobar septal thickening, lymph node promised patients; HIV-infect-
and mucous membranes (45– enlargement (hilar), (very) rarely pleural ed patients more often present
65%), organ abscess formations, effusion, nodule predominance towards the with fever, lymphadenopathy,
fever (50–80%), pulmonary inferior pulmonary lobes. hepatosplenomegaly, and cuta-
(84%), bone (5%), CNS (menin- Nodule diameters from 0.5 to 3 cm with neous lesions
gomyelitis) (2–3%), and adrenal ill-defined contour cavitation, miliary pat- Relapses usually occur within 3
gland tern (rare), diffuse interstitial infiltration, years after initial treatment
posttreatment fibrosis, and scars
Primary infection: lung, pleura, Primary infection: unilateral infiltrate with Radiographic findings may
skin, and musculoskeletal hilar adenopathy, parapneumonic effusion, persist for years
Extrapulmonary: skin and soft tis- thin-walled cavities or nodules Residual pulmonary nodules
sue, skeleton, CNS (meninges and Chronic infection: and thin-walled cavities usually
spinal cord), eye, heart, liver, coccidioidal cavities (in 2–8% of patients), have no clinical consequences
kidneys, prostate complicated by CPA or abscess formation, Rarely cavity ruptures after
fistulae, persistent pneumonia, chronic fi- years with broncho-pleural
bro-cavitary changes (mixtures of infiltrates, fistula
cavitation, and hilar adenopathy), diffuse More severe in immunocom-
reticulonodular (miliary) pneumonia promised, elderly, diabetes
mellitus, pregnancy
Consolidations, interstitial infiltrations,
nodules and masses, involvement of mul-
bone and joints, CNS, and geni- tiple or single lobes, less adenopathy
tourinary
Skin and lymphatic, pulmonary,
osteoarticular, CNS
Reticuloendothelial system (liver, Interstitial to alveola infiltrates, reticulo-
spleen, lymph nodes, bone mar- nodular pattern, nodules, miliary pattern
row), skin, pulmonary, gastroin-
testinal, osteoarticular, CNS
Fig. 3. Axial CT scan of the chest showing bipulmonary, solid nod-
ules (white arrows) in a 27-year-old female biology student with
cough and fever lasting for several weeks after returning from a
field trip exploring bat caves in Central America. Diagnosis of pul-
monary histoplasmosis was established by positive culture and
Histoplasma capsulatum var. capsulatum-specific PCR from lung
tissue as well as positive H. capsulatum antibody detection. Histo-
pathology from lung tissue showed noncaseating granulomas with
giant cells, but without evidence of fungi (Grocott’s methenamine
silver stain). Cytology and routine microbiological cultures from
bronchoalveolar lavage fluid revealed no evidence of fungi.
Salzer et al.
Table 3. Diagnostic tests to establish diagnosis of endemic mycoses and histological appearance

Culture Histopathology Antigen detection Serology Molecular methods

Histoplasmosis Isolation from clinical specimens
remains gold standard (cave: dan-
ger of laboratory infection by Histo-
plasma capsulatum in mycel phase)
Tuberculoid granuloma with intracellular
yeast cells (can be mistaken for trypano-
soma, leishmania amastigotes, or Talaromy-
ces marneffei yeast cells)
A polyclonal antibody-based antigen test
in urine is commercially available in the
USA; cross-reactivity with other fungal
infections, including Blastomyces dermatiti-
dis, CPA may occur;
a monoclonal antibody-based lateral flow
antigen detection assay is currently under
evaluation
Antibody detection by ID, CF, PCR assays available in
or Western blot available, high reference laboratories,
specificity, however, results may not standardized
be falsely negative in immuno-
suppressed patients and in those
who present with acute disease

Paracoccioido- Cultures are diagnostic, but can Tuberculoid granuloma with multipolar Antigen detection in BAL has been de- DID, CIE, ELISA, and immu- PCR assays available in
mycosis take up to a month to grow budding yeast cells (“ship-pilot´s wheel” or scribed (gp43, not expressed in Paracoc- noblotting; utility is hampered reference laboratories,
“Mickey Mouse head”) cidioides lutzii), but not standardized by cross-reactivity with other but are not standardized
endemic fungi; inaccuracies in
the diagnosis in P. lutzii infec-
tion.

Coccidioido- Culture confirms the diagnosis; Tuberculoid granuloma with spherules Coccidioides galactomannan antigen test ID and CF; Most clinical infec- PCR assays are being
mycosis Cultures must be manipulated in a (60–100 µm with endospores of 2–5 µm) available in reference laboratories; low tions diagnosed serologically in evaluated
biosafety level III laboratory sensitivity (70%) the setting of a compatible clini-
cal syndrome

Blastomycosis Culture confirms the diagnosis; Tuberculoid granuloma with unipolar EIA for polysaccharide cell wall antigen ID and CF have no role in diag- PCR assays have not been
diagnostic yield is high for both broad-based budding yeast cells commercially available; high sensitivity nosis because poor sensitivity tested in large studies
bronchoscopy and sputum samples, (93%) but low specificity (79%) due to and significant cross reactivity
but takes 1–4 weeks cross-reaction with other fungi

Sporotrichosis Isolation from clinical specimens
remains gold standard; clinical
specimens should be inoculated on
Sabouraud agar and incubated at
room temperature for 1–4 weeks
Necrotizing granulomas, paucity of yeasts Not available One EIA has been developed, PCR‐based assays have
but is not available been developed, yet to be
evaluated

Talaromycosis T. marneffei can be cultured from
blood and other clinical samples,
but can take up to 14 days for iden-
tification
Binary fission yeasts within histiocytes or
extracellularly; T. marneffei may be con-
fused with H. capsulatum, but has a central
transverse septum unlike any other com-
mon pathogenic yeasts
EIAs detecting mannoprotein in the fungal Antibody detection by ID, EIA, PCR‐based assays have
cell wall in blood and urine, have high or Western blot available; low been developed, low
sensitivity and specificity but are not com- sensitivity in HIV-infected sensitivities (60–70%),
mercially available yet; patients not standardized
over 80% of patients with disseminated
talaromycosis are galactomannan antigen
(“Aspergillus spp.”) positive in sera

BAL, bronchoalveolar lavage; CF, complement fixation; CIE, counterimmunoelectrophoresis; CPA, chronic pulmonary aspergillosis; DID, double immunodiffusion technique; EIA, enzyme immunoassay;
ELISA, enzyme-linked immunosorbent assay; ID, immunodiffusion; PCR, polymerase chain reaction.

a b

Fig. 4. a Chest X-ray showing bipulmonary diffuse pulmonary micronodules sparing the periphery in a 50-year-
old HIV-positive male presenting with cough and dyspnea. b Corresponding axial CT scan of the chest showing
diffuse, confluent perihilar pulmonary nodules. Biopsy from ulcerative lesions of the larynx and the anus dem-
onstrated Histoplasma capsulatum.

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Pulmonary Disease DOI: 10.1159/000489501
 The clinical manifestations vary depending on the im-
mune status of the host and the infectious dose (Table 2).
The disease is usually asymptomatic or manifests as an
acute respiratory illness that is self-limiting in immuno-
competent persons, but it can result in severe illness with
progressive pulmonary disease or disseminated infec-
tion, especially in immunocompromised persons. In
most cases histoplasmosis presents with various pulmo-
nary symptoms, often as a subacute pulmonary infection
3–21 days after exposure. Symptoms are usually mild.
Fever, chills, headache, myalgia, anorexia, cough, and
chest pain may occur in the more heavily exposed indi-
viduals. Pulmonary histoplasmosis is generally classified
according to radiographical appearance and includes (1)
Table 4. Treatment regimens for pulmonary endemic mycoses based on available guidelines
Recommended regimen
Histoplasmosis Mild to moderate: Itraconazole 200 mg p.o. t.i.d. for 3 days
(loading dose) followed by 200 mg p.o. once daily or b.i.d.
Severe: Liposomal amphotericin B 3–5 mg/kg/day IV (pre-
ferred) for 2 weeks or until clinical improvement followed by
itraconazole (see above)
or
Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV for 1-2
weeks or until clinical improvement followed by itraconazole
(see above)
Paracoccidio- Mild to moderate: Itraconazole 200 mg p.o. once daily
idomycosis Severe: Liposomal amphotericin B 3–5 mg/kg/day IV (pre-
ferred) until clinical improvement followed by itraconazole (see
above)
or
Deoxycholate amphotericin B 0.5–0.7 mg/kg/day IV until clini-
cal improvement followed by itraconazole (see above)
Coccidio- Mild: No treatment recommended
idomycosis Severe: Fluconazole 400 mg p.o. once daily
Severe disease in immunocompromised hosts: Liposomal am-
photericin B 4–6 mg/kg/day plus fluconazole 400 mg daily until
clinical improvement
or
Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV plus fluco-
nazole 400 mg daily until clinical improvement
Blastomycosis Mild to moderate: Itraconazole 200 mg p.o. t.i.d. for 3 days
(loading dose), followed by 200 mg p.o. b.i.d.
Severe: Liposomal amphotericin B 3-5 mg/kg/day IV (pre-
ferred) for 1–2 weeks or until clinical improvement followed by
itraconazole (see above)
or
Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV until clini-
cal improvement followed by itraconazole (see above)
Sporotrichosis Mild to moderate: Itraconazole 200 mg p.o. b.i.d.
Severe: Liposomal amphotericin B 3–5 mg/kg/day IV until
clinical improvement followed by itraconazole (see above)
or
Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV until clini-
cal improvement followed by itraconazole (see above)
Talaromycosis Regardless of disease severity: Liposomal amphotericin B 3–5
mg/kg/day IV for 1–2 weeks followed by itraconazole (see
above)
or
Deoxycholate amphotericin B 0.7–1.0 mg/kg/day IV for 2
weeks or until clinical improvement followed by itraconazole
(see above)
CPA, chronic pulmonary aspergillosis; b.i.d., twice a day; p.o., per os; t.i.d., three times a day; IV, intravenously.
288 Respiration 2018;96:283–301
DOI: 10.1159/000489501
acute diffuse pulmonary disease with diffuse infiltrates
on chest imaging, (2) acute localized pulmonary disease
with localized infiltrates and mediastinal lymphadenop-
athy, (3) chronic cavitary pulmonary histoplasmosis, and
(4) mediastinal syndromes (e.g., mediastinitis, fibrosis),
broncholithiasis, or pulmonary nodules (Fig. 1–4) [2, 4].
Disseminated histoplasmosis occurs primarily in pa-
tients with underlying immunocompromising disorders,
in particular those with impairment of T-cell immunity
such as in HIV infection, in patients who are treated with
TNF-α inhibitors, and in patients with IFN-γ receptor
deficiency [5, 6]. In endemic areas or in travelers with an
appropriate travel history, pulmonary histoplasmosis
should be considered as an important differential diag-
Duration Alternative treatment Commentary
6–12 weeks Posaconazole 400 mg (oral suspension) b.i.d. – No treatment recommended for mild symptoms <4
[58] weeks or for pulmonary nodules or broncholithiasis or
Voriconazole 200 mg p.o. b.i.d. [59] mediastinal fibrosis only
Isavuconazole 200 mg t.i.d. for 2 days, fol- – Oral solution has a better absorption – 12-month
lowed by 200 mg once daily [60] treatment duration is recommended in patients with
chronic (cavitary) histoplasmosis
– Surgery (e.g., lobectomy) should be discussed in pa-
tients with residual pulmonary cavities (CAVE: risk of
relapse or long-term complications such as CPA)
– Echinocandins are not effective
12 months Cotimoxazole 960 mg p.o. b.i.d. or t.i.d. – Cotrimoxazole increases treatment duration to 18–24
(9–18 month) months
3–6 months Itraconazole 200 mg p.o. b.i.d. – Patients with a mild disease usually recover without
antifungal treatment
12 months Liposomal amphotericin B 3–5 mg/kg/day IV – Fluconazole has fewer side effects and drug interac-
tions compared to itraconazole
– Liposomal amphotericin B as an alternative for more
severe cases
– Treatment duration of 6–12 months in immunocom-
promised patients
6–12 months Fluconazole 400–800 mg p.o. per day – Alternative treatment with ketoconazole or flucon-
Voriconazole 200 to 400 mg p.o. b.i.d. after azole less effective
amphotericin B therapy for CNS disease – CAVE: higher toxicity of ketoconazole
– Voriconazole or posaconazole may also be effective,
but lack of evidence
≥12 months Fluconazole 400–800 mg p.o. daily – Surgical resection should be discussed
– Alternative treatment less effective
12 weeks Voriconazole 400 mg b.i.d. on day 1 followed – Initial treatment with amphotericin B deoxycholate
by 200 mg b.i.d. for 12 weeks reduces mortality by 50% compared to itraconazole at 6
Itraconazole 200 mg p.o. t.i.d. for 3 days, months in HIV-associated talaromycosis in the IVAP
followed by 200 mg p.o. b.i.d. for 12 weeks for trial [52]
patients unable to tolerate or have no access
to amphotericin B
Salzer et al.
nosis to pulmonary tuberculosis, malignancy and sar-
coidosis. Extrapulmonary manifestations such as peri-
carditis, arthritis/arthralgia, or erythema nodosum are
also reported.
Coccidioidomycosis
Pulmonary coccidioidomycosis (i.e., valley fever) re-
fers to pulmonary infection by the dimorphic fungi Coc-
cidioides immitis and Coccidioides posadasii (Table 1). It
is endemic in the southwestern parts of the USA (Califor-
nia, Arizona, New Mexico, Utah, and Nevada) and parts
of Central and South America (Mexico, Brazil, Argenti-
current risks of developing chronic pulmonary asper-
gillosis or pulmonary abscesses, or fistulae as long-term
sequelae [7, 12, 13].
Paracoccidioidomycosis
Paracoccidioidomycosis caused by the dimorphic
fungi Paracoccidioides brasiliensis and Paracoccidioides
lutzii is found in certain parts of South America, espe-
cially in Brazil, but also in Argentina, Colombia, Ecua-

Color version available online

na). Outbreaks have been reported in military trainees, in
archeological workers, or have been associated with dust
storms, as well as laboratory-acquired infection [7–11].
Approximately two-thirds of infected persons re-
main asymptomatic or develop self-limiting respiratory
symptoms. When symptomatic, pulmonary involve-
ment is common (>95% of all cases). The most common
clinical manifestations are chest pain, cough, fever,
weight loss, and fatigue, often associated with dermato-
logical manifestations including erythema nodosum
(Fig.  5) or erythema multiforme and rheumatological
manifestations including myalgia and arthralgia. Ra-
diological presentation can vary considerably (Table 2)
(Fig. 6, 7). The disease can spread from the lungs hema-
togenously to bones, joints, skin, and the central ner-
vous system. Some patients have persistent pulmonary
complications including residual pulmonary nodules
(coccidioidomas), fibrosis and cavities, with the con- Fig. 5. Erythema nodosum in a patient with coccidioidomycosis.

a b

Fig. 6. a Chest X-ray of a 30-year-old man with coccidioidomycosis showing bilateral large confluent infiltrates
predominantly located in the lower lung fields. b Corresponding axial CT scan of the chest shows multiple large
nodules. The patient presented with intense asthenia, cough, and chest pain. Clinical symptoms started 7 days
after having participated in armadillo hunting in northeastern Brazil.

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dor, Peru, and Venezuela [14, 15]. It is usually seen in
individuals working in rural areas (e.g., farmers). Out-
breaks of paracoccidioidomycosis have been reported
[16, 17].
Infection is often asymptomatic. Symptomatic disease
is divided in an acute/subacute form and a chronic form.
The acute form occurs in children and young adults (ju-
venile form), develops more rapidly, usually within 45
days after exposure, is progressive and more severe. Pa-
tients present with infection of the lymphatic system,
Fig. 7. A 50-year-old female traveled for 1 week on a retreat to a
lodge in the Arizona desert. Eleven days after return, she presented
with cough, dyspnea, and fever. She was diagnosed as having coc-
cidioidomycosis. Soon afterwards, she developed typical erythema
nodosum lesions on her legs. Her chest X-ray showed faint reticu-
lar opacities in the right upper lobe, as well as a nodular opacity in
the right apex. A CT scan shows a cavitating nodule in the right
apex. Mediastinal images revealed multiple enlarged lymph nodes.
manifested by enlarged lymph nodes that can develop
into abscesses or draining fistulae. Important differential
diagnoses such as visceral leishmaniasis or tuberculosis
should be considered. The disease can disseminate
through the reticuloendothelial system manifested as
hepatosplenomegaly and bone marrow dysfunction.
The chronic (adult) form represents reactivation of the
primary infection and develops over months to years.
Pulmonary involvement is the most frequent manifesta-
tion, but the disease may affect any other organs
(Fig. 8–10). Patients usually present with dry cough and
dyspnea and can have extensive radiographic findings
varying from localized consolidations, nodules, cavities,
and bilateral infiltrates to chronic findings of septal or
interlobular thickening consistent with fibrosis. Hema-
togenous dissemination to the oropharynx area occurs
over 50% of the time and is manifested as granulomatous
ulcerative oropharyngeal lesions called “mulberry-like”
stomatitis (Fig.  11). Infection by P. brasiliensis occurs
mainly by inhalation. Patients often present with pulmo-
nary symptoms associated with fever, leukocytosis with
hypereosinophilia, and radiological signs of apical pleural
and pulmonary lesions (Fig. 12). Enlarged lymph nodes
are not a common finding, except in children. Immuno-
compromised patients such as those with HIV infection,
cancer, malnutrition, alcoholism, or drug abuse are at risk
for the development of disseminated disease with a more
rapid progression with involvement of the lung, liver,
lymph nodes, and skin. Occasionally it is found in travel-
ers [18].

a b

Fig. 8. Axial CT scans of the chest showing various types of lesions of paracoccidioidomycosis in a 42-year-old
farmer presenting with fever, asthenia, severe weight loss, dysphagia, and cough. Physical examination showed
diffuse enlarged lymph nodes, notably in the mid and posterior cervical chains and a small ulcerated lesion in the
pharynx. Microscopy of bronchoalveolar lavage showed Paracoccidioides brasiliensis. a Axial CT scan of the chest
shows nodules associated with ground-glass opacities and consolidations beside cavities with irregular walls.
b The larger cavity on the left side shows a small round mass inside. Basal parts of the lung show peripheral con-
fluent opacities without cavities, some displaying the reverse halo sign.

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 Color version available online
a b

Fig. 9. a Fistulated and enlarged cervical lymph node in a 60-year-old farmer from Brazil presenting with cough,
dysphagia, and hoarseness since 6 months. Microscopy of lymph node material revealed Paracoccidioides brasil-
iensis. b Axial CT scan of the chest at the carina level shows nodules and consolidation with a thickened bron-
chovascular bundle (white arrows) in addition to areas of cicatricial emphysema.

Color version available online

a b

c d

Fig. 10. a Chest X-ray showing diffuse micronodular interstitial infiltrates predominantly in the lower fields of
the lung in a 35-year-old farmer in the interior of the state of Rio de Janeiro. He presented with fever for about
40 days, asthenia, and severe weight loss. Immunodiffusion was positive for Paracoccidioides brasiliensis. b For-
ty days later the X-ray showed a progression of the pulmonary lesions with volumetric reduction and hypertrans-
parent images. c Axial CT scan of the chest showing extensive areas of cicatricial emphysema in the left upper
lobe. The patient developed respiratory insufficiency and died. d Postmortem biopsy revealed budding cells of P.
brasiliensis (silver stain).

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 Color version available online
a b

c d

Fig. 11. a “Mulberry-like” stomatitis in a 44-year-old female patient from Brazil with paracoccidioidomycosis.
She was admitted with the suspicion of oral pharyngeal cancer. b X-ray of the chest showed localized infiltrates
in the lower and middle fields of both lungs (left > right). c Corresponding CT scan of the chest shows localized
consolidations with bounded ground-glass opacities. d After 1 year of antifungal treatment with itraconazole
radiological findings were resolved.

Blastomycosis very diverse radiological findings, which include alveolar

The causative pathogens for blastomycosis are the di-
morphic fungi Blastomyces dermatitidis and Blastomyces
gilchristii, which are found in humid soil containing de-
caying vegetation or decomposed wood and are associ-
ated with freshwater drainage basins [19]. It is reported
mainly in North America and in Africa, but occasionally
has also been reported in Central and South America,
Mexico, India, and the Middle East. Blastomycosis has
caused a number of outbreaks [20].
After inhalation of the fungus, the most commonly af-
fected organ is the lung followed by the skin, genitouri-
nary tract, and central nervous system (Fig. 13) [21]. Lung
involvement is classified as acute or chronic pneumonia.
Acute blastomycosis pneumonia cannot be readily distin-
guished from viral or bacterial pneumonia [21], and has
infiltrates, consolidation with or without cavitation, mili-
tary or reticulonodular patterns, and small pleural effu-
sions. Acute pneumonia can potentially lead to acute re-
spiratory distress syndrome with multiorgan failure and
mortality rates of 50%. The clinical appearance of chron-
ic blastomycosis pneumonia is similar to tuberculosis,
lung cancer, or histoplasmosis. The radiological pattern
is often described as alveola or fibronodular infiltrations,
mainly with an upper lobe distribution [21]. The absence
of mediastinal lymph node involvement can be helpful in
distinguishing blastomycosis from histoplasmosis.
Sporotrichosis
The dimorphic fungus Sporothrix schenckii causes
sporotrichosis, a chronic infection mainly found in

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 a b
Fig. 12. Different radiological manifestations of paracoccidioidomycosis in patients coming from rural regions
of Brazil. X-rays of the chest showing extensive consolidating infiltrates of both lungs (a), infiltrates predomi-
nately located in the mid and lower fields of both lungs (b), and a more micronodular pattern of distribution
mimicking miliary tuberculosis (c).
healthy individuals with outdoor activities that involve
inoculation of soil through the skin or subcutaneous tis-
sues such as gardening and landscaping [22, 23]. It is
found worldwide in temperate, but also tropical and sub-
tropical areas. Larger outbreaks of sporotrichosis have
been reported [24].
Disseminated disease involving the central nervous sys-
tem may occur in immunosuppressed patients (e.g. HIV/
AIDS, alcoholism, diabetes) [25]. Infection is either due to
inhalation of spores or through skin inoculation. The most
common form is the lympho-cutaneous manifestation,
which has only mild systemic involvement (Fig. 14). Pul-
monary involvement usually occurs in patients with chron-
ic obstructive pulmonary disease and alcohol use, and pro-
gresses to death if untreated. Symptoms and radiographic
appearance are similar to pulmonary tuberculosis and oth-
er chronic fungal infections (Fig. 15) [26].
Talaromycosis
Talaromycosis is caused by the dimorphic fungus Ta-
laromyces marneffei (formally Penicillium marneffei) and
is endemic in South-East Asia, southern China and north-
eastern India [27]. Talaromycosis mainly affects immu-
nocompromised patients living or traveling to these re-
gions, in particular patients with advanced HIV infection,
with hematological malignancy, and patients undergoing
immunosuppressive therapy [28, 29]. Although bamboo
rats are a natural reservoir, infection risk is not associated
with exposure to bamboo rats but is associated with high
humidity and exposure to plants and farmed animals in
highland regions [30].
Systemic Endemic Mycoses Causing
Pulmonary Disease
c
The infection has an insidious onset over weeks to
months. The clinical symptoms range from mild to mod-
erate infection with localized disease, to disseminated in-
fection with multiple organ involvement, to severe dis-
ease including respiratory failure and shock [31]. The
most prominent clinical features in HIV-infected pa-
tients are fever, weight loss, anemia, generalized lymph-
adenopathy, hepatomegaly, and splenomegaly [31]. Typ-
ical central umbilicated skin lesions are present in 70% of
HIV-infected and up to 40% of non-HIV-infected pa-
tients and aid in the rapid diagnosis [32]. Besides the skin
and reticuloendothelial system involvement, talaromyco-
sis often invade the gastrointestinal tract with oropharyn-
geal ulcerations and diarrhea, the pulmonary system with
progressive respiratory failure, and occasionally the cen-
tral nervous system with meningoencephalitis. Arthritis
and osteomyelitis are more commonly observed in non-
HIV-infected patients. The radiological appearance is di-
verse and includes interstitial to alveolar infiltrates, or
both (Fig.  16), and reticulonodular consolidation, with
occasionally a miliary pattern similar to tuberculosis
(Fig. 17) [33].
Diagnosis
In low-prevalence settings the diagnostic workup for
endemic mycoses is challenged by the availability of diag-
nostic tests, and will differ widely from site to site. In ad-
dition, the positive predictive values of some nonculture-
based tests will be significantly lower than in endemic set-
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 Color version available online
a

b c d

Fig. 13. a, b Chest X-rays of a 42-year-old male resident of Mon-
treal, Canada, showing extensive consolidation mostly involving
the superior segment (S6) of the right lower lobe. He was also a
recreational hunter in the region of the St. Laurence river valley.
He presented with a 2-month history of cough, mild hemoptysis,
and intermittent fevers. Biopsy revealed budding yeast cells, and
culture from a bronchoalveolar lavage grew Blastomyces derma-
titidis. c, d Two male patients with slowly growing, minimally
painful skin lesions, unresponsive to several courses of antibacte-
rial agents. Exposures were most like to be in rural regions of
south-western Quebec (c) and central Manitoba (d), Canada. Bi-
opsy specimens revealed noncaseating granulomatous changes,
and cultures from biopsy specimens grew Blastomyces. There were
no respiratory symptoms, but in both cases small nodular lesions
were seen on pulmonary imaging, which resolved with antifungal
treatment.

Color version available online

Fig. 14. Slowly progressive skin lesions in a

24-year-old male traveler returning from
several months in India, where he partici-
pated in gardening activities at his resi-
dence. The initial ulcerating verrucous
lesion appeared on the tip of 4th digit,
followed by the appearance of popular/
nodular lesions on the forearm. Culture
from the fingertip ulcer grew Sporothrix
schenkii.

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a
d e
Fig. 15. a Pyogenic and ulcerated cutaneous lesion of thighs of a
24-year-old male pig caregiver in Brazil, reported onset of the dis-
ease about 4 months ago complaining of sporadic fever, cough,
asthenia, and weight loss. Chest X-ray (b) and axial CT scans (c,
d) show irregularly shaped thick-walled cavitations of different
tings. As such, awareness of geographical distribution
and exposure risks of endemic mycoses, along with case
discussion involving an interdisciplinary team compris-
ing infectious disease specialists, microbiologists, radiol-
ogists, and pathologists are paramount to making the
diagnosis [34]. Culture of most of these organisms (par-
Systemic Endemic Mycoses Causing
Pulmonary Disease
Color version available online
sizes. c Small nodular cavities can be seen in both lungs, some par-
tially occupied by material with soft tissue density. d A large thick-
walled cavity of the left lung with an irregular wall can be seen. e
Culture of biopsies harvested from the cutaneous lesion demon-
strated growth of Sporothrix schenkii.
ticularly for coccidioides) requires biosafety level 3
laboratory precautions, and the laboratory should be
alerted when infection is suspected. Table 3 summarizes
diagnostic tests to establish the diagnosis of endemic my-
coses.
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Fig. 16. Progressive bilateral alveola and interstitial infiltrates with
air bronchogram signs in the left lower lobe in a 32-year-old man
who presented to the Hospital for Tropical Diseases in Ho Chi
Minh City in 2015 with 2 weeks of fever, weight loss, fatigue,
cough, difficulty breathing when laying down, abdominal pain,
and diffuse central umbilicated nodules on his face, body, and ex-
tremities. He was diagnosed with HIV and had a CD4 cell count of
3 cells/mm3. His skin culture grew Talaromyces marneffei, while
sputum and blood culture showed no growth.
Histoplasmosis
While evidence is too scarce to recommend a specific
diagnostic scheme, a combination of at least two of the
following diagnostic methods seems reasonable:
(a) Histology. Typically, biopsy specimens show tuber-
culoid granulomas with many polymorphonuclear leuco-
cytes and histiocytes with intracellular yeast cells. Differ-
entiation from tuberculosis or sarcoidosis may be diffi-
cult – especially in low-prevalence settings. Sensitivity
and specificity of histology are highly dependent on the
pathologist’s experience, but may be enhanced by fungal
stains, e.g., Gomori methenamine silver and periodic
acid–Schiff stains [35]. The tiny yeast forms (approx.
2 µm) are easily missed.
(b) Culture. Sensitivity depends on the clinical mani-
festation, the immunity status of the host, and the fungal
burden – it is low in patients with acute pulmonary his-
toplasmosis [36]. Repeated sputum and/or bronchoalve-
olar lavage (BAL) and/or bone marrow aspirate for cul-
tures and a long incubation period of cultures (up to 6
weeks) may be necessary.
(c) Antigen test. An enzyme immunoassay (EIA) for
detection of H. capsulatum galactomannan from blood,
urine, and BAL is commercially available in the USA [37].
In a multicenter study with 111 patients with proven pro-
gressive disseminated histoplasmosis, the EIA reached a
sensitivity of 91% and a specificity of 99% in urine [38].
Sensitivity seems to be lower in immunocompetent hosts,
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probably due to a lower fungal burden. Similarly, sensi-
tivity is lower in localized pulmonary disease. Of note,
there is strong cross-reactivity with other endemic myco-
ses such as blastomycosis, paracoccidioidomycosis, and
talaromycosis [38]. Histoplasma sp. contain galactoman-
nan in the cell wall, and may give a positive result in
galactomannan assays used for the diagnosis of asper­
gillosis.
(d) Antibody test. Histoplasma-specific antibodies can
be detected either by immunodiffusion, by complement
fixation or by EIA, and a commercial assay is available in
the USA. Due to the time needed for the development of
specific antibodies (up to 3 months) a negative test does
not always exclude histoplasmosis. In contrast to antigen
testing, sensitivity is higher in immunocompetent hosts,
and therefore antigen and antibody are often used togeth-
er to maximize overall sensitivity [38]. The histoplasmin
delayed-type hypersensitivity skin test is used mainly for
epidemiological studies, and is not sufficiently accurate
for use in individual case diagnosis
(e) PCR. Several protocols using a variety of molecular
targets have been described in the literature, but the role
for PCR in the diagnostic workup is not yet certain [34].
Fluorescence in situ hybridization (FISH) has also been
described.
Coccidioidomycosis
Serology is the main method for diagnosing Coccid-
iodes infection in the USA, where EIAs for specific IgM
and IgG are commercially available [39]. A confirmatory
immunodiffusion test should be ordered after a positive
EIA due to higher specificity [40]. In contrast to most
other infectious diseases, anti-coccidioidal antibodies
will be positive only in the case of an ongoing or recent
infection. A limitation is that antibodies will only form
after a latency period of several weeks; therefore the ab-
sence of antibodies does not exclude infection in the ear-
ly course of illness. Direct microscopic examination of
clinical specimens and/or culture may be a faster means
of diagnosing Coccidiodes infections [39]. Fungal growth
can be observed within 1 week, and identification is fol-
lowed by a commercially available Genprobe with detects
C. immitis-specific nucleic acid sequence. To assert dis-
seminated coccidioidomycosis, it is usually necessary to
visualize fungi in extrapulmonary biopsy specimens [39].
Paracoccidioidomycosis
A definite diagnosis of paracoccidioidomycosis can be
made after direct microscopic examination of the charac-
teristic yeast forms in tissue samples (sputum, ascites, bi-
Salzer et al.
 Color version available online
a b c

Fig. 17. a A 30-year-old man who presented to the Hospital for Tropical Diseases in Ho Chi Minh City in 2013
with 1 month of fever, weight loss of 12 kg, dry cough, shortness of breath, enlarged cervical lymph nodes, hepa-
tosplenomegaly, and multiple central umbilicated nodules on his face and trunk. He was diagnosed with HIV
and had a CD4 count of 12 cells/mm3. b X-ray of the chest showed a diffuse micronodular interstitial pattern
consistent with miliary talaromycosis. Cultures from the lymph node, skin lesions, and blood were all positive
for Talaromyces marneffei. c T. marneffei yeast cells obtained from a Giemsa-stained touch skin smear were seen
under the microscope.

opsies, scraping of skin lesion, etc.) stained with fungal
stains (large yeast cells surrounded with multipolar bud-
ding daughter cells resembling a “Mickey mouse head” or
a “steering-wheel”) or by culturing the organism [14].
Culture can take up to 1 month to grow; therefore direct
microscopy remains the cornerstone in the diagnosis of
paracoccidiodes infection. Serological methods, in par-
ticular the quantitative immunodiffusion method, are
widely available in the endemic regions. However, in
most cases serology is not necessary for diagnosing para-
coccidioidomycosis. While it can be a useful tool to mon-
itor treatment success, so far serologic diagnosis is not
standardized, and results from different laboratories may
be conflicting [41]. There are no validated serological
techniques for diagnosis of infection with P. lutzii.
Blastomycosis
Direct proof of Blastomyces infection – either by cul-
ture or visualization of the yeast forms – is necessary for
a definite diagnosis of blastomycosis and the method of
choice [42]. Culturing Blastomyces organisms from respi-
ratory samples of affected patients has a high sensitivity
of around 90%, but takes 1–4 weeks. Direct microscopic
examination of typical yeast organisms with broad-based
buds is characteristic of Blastomyces; however, micros-
copy has a low diagnostic yield of up to 40%. Serological
tests for blastomycosis are hampered by their low sensi-
tivities and their lack of specificity due to cross-reactivity
against other endemic mycoses, in particular against his-
toplasmosis [43]. The utility of PCR assays for the detec-
tion of B. dermatidis has not yet been validated in large
clinical studies. Finally, similar to histoplasmosis, a single
antigen detection assay is available in the USA [44]. The
assay has a high sensitivity of around 90%, but also lacks
specificity due to cross-reactivity – especially with histo-
plasmosis.
Sporotrichosis
Culture is the best option in the diagnostic workup of
suspected sporotrichosis [45]. Culture is very sensitive,
and visible growth can be seen within 1 week. S. schenckii
is not considered a colonizer, thus a positive clinical sam-
ple is diagnostic. While histopathology may help in show-
ing a pyogenic and granulomatous picture, the organism
can only rarely be visualized due to the paucity of or­
ganisms [45]. No validated serology or PCR is currently
available.
Talaromycosis
T. marneffei can be cultured from blood and clinical
samples using standard media for bacteria culture
(Fig. 18). As growth may take approximately 1 week, a
presumptive diagnosis can be made based on the visual-
ization of binary fission yeasts on fungal staining of skin
scraping, sputum smear, or biopsies [46]. This enables the
initiation of antifungal therapy before confirmation of

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Color version available online
25°C SDA medium
a b
37°C SDA medium
c d
Fig. 18. Morphology of Talaromyces marneffei colonies on Sab-
ouraud agar (SDA) medium and the fungus under the microscope
at 25 ° C (a, b) and at 37 ° C (c, d).
culture results. Rapid diagnostic assays are being devel-
oped including several monoclonal antibody-based anti-
gen detection EIAs, which have high sensitivity and spec-
ificity, and are being evaluated as rapid diagnostic tests
[47, 48]. Real-time PCR assays have been developed but
sensitivities are currently insufficient (60–70%) to be
clinically useful.
Management
For most systemic endemic mycoses causing pulmo-
nary disease including histoplasmosis, paracoccidioido-
mycosis, blastomycosis, sporotrichosis, and talaromyco-
sis, experts generally recommend antifungal treatment
with itraconazole. It is the treatment of choice for mild to
moderate disease manifestations (Table 4) [14, 22, 49–
52]. Mild cases of histoplasmosis with symptoms less than
4 weeks usually do not require antifungal treatment, while
paracoccidioidomycosis, blastomycosis, sporotrichosis,
and talaromycosis should be treated when diagnosed [14,
22, 50]. Disseminated talaromycoses should be treated as
soon as possible to decrease mortality, and initial therapy
with amphotericin B deoxycholate has been shown to be
superior to itraconazole in the IVAP trial in Vietnam
[53]. For all endemic mycoses with severe disease mani-
festations, amphotericin B is recommended as initial
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therapy followed by itraconazole consolidation therapy.
Generally, lipid formulations of amphotericin B are pre-
ferred due to their relatively lower toxicity (infusion re-
lated reactions, renal failure, electrolyte disturbance, and
anemia). High-dose fluconazole is recommended as the
treatment of choice for severe coccidioidomycosis infec-
tions, while patients with a mild disease usually recover
without any antifungal treatment [39]. Little evidence ex-
ists with alternative treatment strategies and the efficacy
of different antifungal drugs can differ considerably be-
tween endemic mycoses and between different manifes-
tations within each endemic mycosis. Table 4 summa-
rizes current antifungal treatment recommendations
according to available guidelines.
Duration of Itraconazole Treatment
Duration of itraconazole treatment strongly depends
on the specific endemic mycoses, clinical syndrome, and
host immune factors (Table 4). Histoplasmosis and tal-
aromycosis usually require a period of 2 weeks of induc-
tion therapy followed by 6–12 weeks of consolidated
treatment, while paracoccidioidomycosis and sporotri-
chosis usually require long-term treatment of at least 12
months [14, 51, 52]. Generally, the duration should be
guided by clinical improvement and radiological resolu-
tion. For immunosuppressed persons, secondary pro-
phylaxis is recommended to prevent disease relapse. In
patients with advanced HIV infection, consolidation
therapy with itraconazole is recommended until the
CD4+ T-cell count increases and remains above 100 cells/
mm3 for at least 3–6 months on antiretroviral therapy.
Strategies to mitigate the underlying cause of immuno-
suppression will dictate the duration of secondary pro-
phylaxis (or consolidation therapy). In persons requiring
immunosuppressive therapy, management requires a
balance between strategies to mitigate immunosuppres-
sion and lifelong antifungal prophylaxis.
The treatment duration for a specific endemic mycosis
will differ depending on clinical syndrome and host fac-
tors. Pulmonary histoplasmosis with its different clinical
syndromes is an illustrative example. Asymptomatic pa-
tients with pulmonary nodules usually do not benefit
from antifungal treatment, while symptomatic patients
do. Furthermore, patients with acute diffuse pulmonary
histoplasmosis often require only 6 weeks of antifungal
treatment, while in patients with chronic cavitary histo-
plasmosis long-term treatment of at least 12 months is
recommended. In AIDS patients with pulmonary histo-
plasmosis who do not achieve immune reconstitution
even lifelong treatment may be recommended [54].
Salzer et al.
 Dosage of Itraconazole Treatment
The commonly recommended dosage for itraconazole
consolidation treatment is 200 mg once to twice daily de-
pending on the severity of disease (Table 4). Generally,
the oral solution of itraconazole is preferred due to the
improved absorption compared to capsules and tablets.
However, the itraconazole solution is not well tolerated
due to the osmotic effect of the co-formulated cyclodex-
trin [54]. Gastric acid is required for adequate absorption
of the capsules and tablets, so they should be taken im-
mediately after meals or with an acidic drink. Antacids
should be avoided or taken at least 4–6 h apart from itra-
conazole tablets and capsules. The oral solution of itra-
conazole, however, should be taken on an empty stom-
ach. It is recommended to start itraconazole treatment
with a loading dose of 200 mg 3 times a day for 3 days to
attain adequate drug levels more rapidly. The manufac-
turer labeling recommends a loading dose only for severe
and life-threatening cases, but in these cases the guide-
lines usually recommend initial therapy with amphoteri-
cin B intravenously until clinical improvement before
continuation with oral itraconazole. Because of the vari-
able bioavailability and the potential for drug-drug inter-
actions, TDM is recommended, especially for patients
who have severe disease, critically ill patients in intensive
care unit, patients on multiple drugs including rifampicin
and antiretroviral therapy with nonnucleoside reverse
transcriptase inhibitors and protease inhibitors, and pa-
tients with infections of the central nervous system, eyes
or bones. However, TDM is not universally available and
several limitations have to be considered (e.g., assays are
not standardized, optimal timing of sampling, sample
transportation, unclear reference values) [55].
Amphotericin B Treatment
Early intravenous amphotericin B treatment is recom-
mended for most severe cases of systemic endemic myco-
ses (Table 4). Generally, lipid-formulated amphotericin B
is preferred due to reduced toxicity. However, in many
resource-constrained settings, lipid-formulated ampho-
tericin B is not available or affordable. Deoxycholate am-
photericin B still remains an effective alternative, but
nephrotoxicity is common and should be closely moni-
tored. Toxicity is significantly mitigated by daily saline
and potassium supplementation. The commonly recom-
mended duration of amphotericin B treatment is 1–2
weeks, but strongly depends on the severity of disease and
the clinical condition of the patient. After clinical stabili-
zation of the patient treatment should be changed to itra-
conazole.
Systemic Endemic Mycoses Causing
Pulmonary Disease
Follow-Up and Complications
Azoles strongly influence the enzymatic activity of cy-
tochrome P450 (e.g., CYP3A4), which can lead to consid-
erable drug-drug interactions [56]. TDM can assist in de-
tecting subtherapeutic drug concentrations due to mal­
absorption and drug-drug interaction and in optimizing
individual dosage regimes. Treatment monitoring and
patient follow-up are essential to detect antifungal side
effects, drug-drug interactions, treatment failure, and
pulmonary sequelae. Long-term sequelae such as chronic
pulmonary aspergillosis should be considered in patients
with cavitary destruction of lung parenchyma [12, 57].
Symptoms may persist for several months and a lung
function test (usually showing an obstructive pattern)
may help to monitor the course of disease.
Conclusions
This review article should guide physicians in the di-
agnosis and management of systemic endemic mycoses
causing pulmonary disease. Several aspects have to be
considered.
First, clinical presentation and radiological pattern of
systemic endemic mycoses may mimic other diseases and
are nonspecific. The medical history plays a central role,
especially the travel history and information on risk fac-
tors for potential environmental exposures. Having a
clinical suspicion is critical as it facilitates specific myco-
logical diagnostics and communication with laboratory
personnel on potential biosafety risk (in particular for
Coccidioides spp.). Physicians need to be aware of basic
disease manifestations and the diversity of clinical and
radiological patterns.
Second, even when an endemic mycosis is suspected,
diagnoses may be hampered by the lack of availability of
diagnostic tests, especially in low-prevalence settings.
Consultation with a mycology reference laboratory is rea-
sonable to discuss proper sample collection and available
diagnostic tests. Test results should be interpreted with
consideration for their performance and for the lower
positive predictive values of some of these tests in com-
parison to what are reported from endemic regions. Cul-
ture or histology from clinical samples (e.g., BAL, lung
tissue) is the method of choice for most endemic mycoses.
A combination of different diagnostic methods is reason-
able, and may increase the likelihood of establishing a di-
agnosis.
Third, if antifungal treatment is indicated itraconazole
(or fluconazole in the case of coccidioidomycoses) is the
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DOI: 10.1159/000489501
treatment of choice in mild to moderate cases, except for In low-prevalence settings it is advisable to discuss pa-
talaromycosis, where amphotericin B should be the initial tients with suspected endemic mycoses with an interdis-
treatment. Early amphotericin B therapy (preferably lipid ciplinary team involving infectious disease specialists,
formulations) is recommended in severe cases until clin- microbiologists, radiologists, and pathologists.
ical stabilization of the patient before changing to itra-
conazole consolidation therapy. Drug-drug interactions,
adverse events, and possible long-term sequelae should Disclosure Statement
be monitored. Duration of treatment differs significantly
between endemic mycoses and depends on the specific The authors have no conflicts of interest to declare.
mycoses, severity of disease, clinical syndrome, and the
immune status of the hosts.

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